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1.
Nat Chem Biol ; 18(12): 1388-1398, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36097295

RESUMEN

The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as 'silent' ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.


Asunto(s)
Cisteína , Proteómica , Transducción de Señal , Citocinas , Isoformas de Proteínas
2.
J Am Chem Soc ; 142(34): 14522-14531, 2020 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-32623882

RESUMEN

Two azobenzenesulfonamide molecules with thermally stable cis configurations resulting from fluorination of positions ortho to the azo group are reported that can differentially regulate the activity of carbonic anhydrase in the trans and cis configurations. These fluorinated probes each use two distinct visible wavelengths (520 and 410 or 460 nm) for isomerization with high photoconversion efficiency. Correspondingly, the cis isomer of these systems is highly stable and persistent (as evidenced by structural studies in solid and solution state), permitting regulation of metalloenzyme activity without continuous irradiation. Herein, we use these probes to demonstrate the visible light mediated bidirectional control over the activity of zinc-dependent carbonic anhydrase in solution as an isolated protein, in intact live cells and in vivo in zebrafish during embryo development.


Asunto(s)
Compuestos Azo/química , Anhidrasas Carbónicas/metabolismo , Luz , Sondas Moleculares/química , Sulfonamidas/química , Animales , Compuestos Azo/síntesis química , Anhidrasas Carbónicas/química , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Simulación del Acoplamiento Molecular , Sondas Moleculares/síntesis química , Estructura Molecular , Sulfonamidas/síntesis química , Pez Cebra/embriología , Bencenosulfonamidas
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